JARID1B-mediated epigenetic regulation of oncogenic signals in oral cancer

JARID1B 介导的口腔癌致癌信号的表观遗传调控

• 批准号: 10190892
• 负责人: Devraj Basu
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190892
• 关键词: Address; Automobile Driving; Biological; Bypass; Cell Therapy; Cells; Collagen; Dependence; Disease; Drug Combinations; Drug Targeting; Drug resistance; Enzymes; Epigenetic Process; Exposure to; Family; Financial compensation; G1/S Transition; G2/M Transition; Genes; Genetic Transcription; Growth; Human; Hyperactivity; Interphase Cell; KDM5B gene; MAP Kinase Gene; MEKs; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mesenchymal; Modeling; Modernization; Molecular Profiling; Mutate; Nature; Neoplasm Metastasis; Oncogenic; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Refractory; Regulation; Regulator Genes; Residual state; Resistance; Role; Signal Transduction; Stains; Testing; Tumorigenicity; Up-Regulation; Work; Xenograft procedure; aggressive therapy; base; cancer cell; cancer therapy; cellular imaging; differential expression; epigenetic regulation; improved; inhibitor/antagonist; malignant mouth neoplasm; malignant state; member; mouth squamous cell carcinoma; mutant; neoplastic cell; non-genetic; novel; patient derived xenograft model; promoter; rapid growth; response; stem-like cell; therapy resistant; trait; tumor behavior; tumor growth; tumor progression; tumorigenic

PROJECT SUMMARY This proposal pursues a basis for our striking observation that oral cancer cells transit between two states with dichotomous PI3K/Akt signals and responses to anti-PI3K drugs. Specifically, maximal Akt activation is found in only a small, slow-cycling fraction of tumor cells, whereas PI3K/Akt signals are suppressed in a distinct, "G0- like" fraction. These G0-like cells are non-dividing but retain high tumorigenic potential and show broad therapy resistance, including escape from PI3K inhibitors. Exiting the G0-like state is regulated by the H3K4me3 demethylase JARIDB, which represses transcription at select promoters but also has ill-defined roles, including ones independent of its catalytic function. JARID1B upregulation in G0-like cells reprograms them into the slow cycling, Akt-hyperactive phenotype, which is sensitive to PI3K inhibitors. The stem cell-like features and enhanced tumorigenicity of this JARID1Bhigh state implicate it in allowing quiescent cells to exert their malignant potential. When JARID1Bhigh cells are depleted by targeting PI3K, G0-like cells could still sustain tumor growth by an alternate, JARID1B-independent pathway for exiting quiescence. By this pathway, G0-like cells may become the critical locus for the compensatory MAPK pathway activation known to underlie PI3K inhibitor resistance. Thus our hypothesis is that G0-like cells are driven by JARID1B to a PI3K-dependent, stem cell-like state with aggressive features but also bypass this state under PI3K inhibition to maintain a central role in sustaining cancer growth. To determine JARID1B's contribution to G0-like cells exiting quiescence, we will delineate its demethylase dependent vs. independent functions and interaction with oncogenic PI3K signals in promoting G1-S transition (aim 1). To pursue JARID1B's contribution to the G0-like state's malignant potential, we will examine JARID1B's potential to promote aggressive tumor behavior by prolonging S/G2 while driving mesenchymal-like differentiation (aim 2). The roles of G0-like and JARID1Bhigh cells will also be defined under PI3K inhibition, where JARID1Bhigh cells may return to a G0-like state that sustains oral cancer progression via MAPK pathway compensation in a JARID1B-independent manner (aim 3). Understanding the mechanisms of transit between the dual states, which together comprise an aggressive, treatment refractory segment of the tumor cell pool, will define new strategies to address the epigenetic plasticity underlying treatment resistance in oral cancer.

项目总结 这一提议为我们的惊人观察奠定了基础，即口腔癌细胞在两个州之间转移 PI3K/Akt信号与抗PI3K药物的反应具体地说，找到了最大Akt激活 仅在一小部分慢周期的肿瘤细胞中，而PI3K/Akt信号在明显的G0- 这些G0样细胞是不分裂的，但保留了很高的致瘤潜力，并显示出广泛的治疗作用 耐药性，包括逃避PI3K抑制剂。退出类G0状态受H3K4me3调节 去甲基酶JARIDB，它在选定的启动子上抑制转录，但也有定义不明确的角色，包括 而不依赖于其催化功能。类G0细胞中JARID1B的上调将它们重新编程为慢速 循环，Akt-过度活跃的表型，对PI3K抑制剂敏感。干细胞样的特征和 这种JARID1B高状态的致瘤性增强意味着它允许静止的细胞发挥其恶性作用 潜力。当靶向PI3K的JARID1BHigh细胞被耗尽时，G0样细胞仍然可以维持肿瘤的生长 通过另一条不依赖JARID1B的途径退出静止。通过这一途径，类G0细胞可能 成为已知PI3K抑制剂背后的MAPK途径代偿激活的关键位置 抵抗。因此，我们的假设是G0样细胞是由JARID1B驱动的依赖PI3K的干细胞样细胞 具有攻击性特征的状态，但也绕过了PI3K抑制下的这种状态，以保持在 维持癌症的生长。为了确定JARID1B对类G0细胞退出静止的贡献，我们将 阐明其去甲基酶依赖与独立的功能以及与癌基因PI3K信号的相互作用 促进G1-S过渡(目标1)。为了追查JARID1B对这个类似G0的州的恶性潜能的贡献， 我们将研究JARID1B通过延长S/G2的驾驶时间来促进侵袭性肿瘤行为的潜力 间充质样分化(目标2)。类G0和JARID1BHigh单元格的角色也将在下定义 PI3K抑制，其中JARID1BHigh细胞可能返回G0样状态，通过 JARID1B非依赖的MAPK途径补偿(目标3)。了解以下机制： 在两个状态之间的过渡，这两个状态共同构成了侵略性的、治疗难治的部分 肿瘤细胞池，将定义新的策略来解决潜在的治疗耐药的表观遗传可塑性 口腔癌。

项目成果

A benchmark for oncologic outcomes and model for lethal recurrence risk after transoral robotic resection of HPV-related oropharyngeal cancers.

• DOI: 10.1016/j.oraloncology.2022.105798
• 发表时间: 2022-04
• 期刊: ORAL ONCOLOGY
• 影响因子: 4.8
• 作者: Brody, Robert M.;Shimunov, David;Cohen, Roger B.;Lin, Alexander;Lukens, John N.;Hartner, Lee;Aggarwal, Charu;Duvvuri, Umamaheswar;Montone, Kathleen T.;Jalaly, Jalal B.;LiVolsi, Virginia A.;Carey, Ryan M.;Shanti, Rabie M.;Rajasekaran, Karthik;Chalian, Ara A.;Rassekh, Christopher H.;Cannady, Steven B.;Newman, Jason G.;O'Malley, Bert W.;Weinstein, Gregory S.;Gimotty, Phyllis A.;Basu, Devraj
• 通讯作者: Basu, Devraj

HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis.

HPV E6通过抑制PGC-1α/ERRα轴来调节口咽癌的治疗反应。

• DOI: 10.1172/jci.insight.159600
• 发表时间: 2022-09-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Sannigrahi, Malay K.;Rajagopalan, Pavithra;Lai, Ling;Liu, Xinyi;Sahu, Varun;Nakagawa, Hiroshi;Jalaly, Jalal B.;Brody, Robert M.;Morgan, Iain M.;Windle, Bradford E.;Wang, Xiaowei;Gimotty, Phyllis A.;Kelly, Daniel P.;White, Elizabeth A.;Basu, Devraj
• 通讯作者: Basu, Devraj